NovoSeven: mode of action and use in acquired haemophilia

Recombinant activated factor VII (rFVIIa, 'NovoSeven') is indicated for the treatment of spontaneous and surgical bleeding in patients with haemophilia A or B with antibodies to factors VIII or IX (FVIII or FIX) worldwide, and in patients with acquired haemophilia in Europe. In vitro cell models have demonstrated that rFVIIa can bind to activated platelets and generate small amounts of Fxa, independent of the presence of tissue factor. The amount of platelet-surface Fxa formed increases with rising concentrations of FVIIa and, at levels of rFVII a that are effective in patients, sufficient platelet surface Fxa is generated partially to restore platelet surface thrombin generation. Acquired haemophilia is a rare but potentially life-threatening condition, caused by the autoimmune reduction of clotting factor levels as a result of the spontaneous development of auto-antibodies directed against the deficient factor. Bleeding into the skin or muscles is common in acquired haemophilia and the associated mortality rate is approximately 20%. rFVIIa has reported efficacy in the treatment of major bleeding episodes in patients with acquired haemophilia, which may be explained by its distinct mechanism of action that induces haemostasis at the site of injury, independent of the presence of FVIII or FIX. Also, the localisation of the action of rFVIIa at the site of injury may explain why it is well tolerated in these patients.     

Experience with use of recombinant activated factor VII

Recombinant activated factor VII (rFVIIa) has recently been introduced for improving haemostasis in haemophiliac patients developing alloantibodies (inhibitors) to factor VIII (FVIII) or factor IX (FIX). We describe the successful management of haemorrhagia with rFVIIa in five different situations: an episode of surgical bleeding in a patient with haemophilia A and non-surgical haemorrhages in four patients with haemophilia A, acquired haemophilia, congenital severe FV defect and pseudo-acquired haemophilia, respectively. In each case, rFVIIa was effective and safe. There is no doubt that rFVIIa is useful in the therapeutic management of patients with antibodies to FVIII or FIX. However, the treatment is expensive and a cost-effectiveness analysis would be useful.     

Recombinant human factor VIIa (rFVIIa) can activate factor FIX on activated platelets

The studies reported here show that factor (F)VIIa can activate factor (F)IX on activated platelets in the absence of tissue factor. Both FIX and FIXa bind to the activated platelet surface with a K(d) of 8 nM and 2 nM, respectively. With factor (F)VIIIa, FIXa binds more tightly to platelets (K(d) 0.6 nM). At rFVIIa concentrations < 100 nm, no direct binding to the activated platelet surface can be detected with electrophoretic light scattering. However, in the presence of FIX, rFVIIa binding to platelets at concentrations as low as 10 nm rFVIIa can be detected. This is reflected by a decrease in the FIX K(d) from 8 to 1.6 nM. When rFVIIa is added to activated platelets in the presence of both FIX and FVIIIa, the K(d) for FIX decreases to 0.6, suggesting that rFVIIa activates FIX on the surface of activated platelets in the absence of tissue factor. The activation of FIX by FVIIa on activated platelets can also be demonstrated by a functional assay for FIXa. These data show that pharmacological doses of rFVIIa result in the direct activation of FIX by rFVIIa to form additional tenase complexes ultimately resulting in improved thrombin generation. These results may explain, at least in part, the mechanism of action of rFVIIa in hemorrhagic conditions seen in otherwise normal patients who develop an acquired coagulopathy due to trauma, surgery or a variety of other events in which rFVIIa has been found to be effective.     

Haemorrhagic complications of thrombocytopenia and oral anticoagulation: is there a role for recombinant activated factor VII?

Recombinant activated factor VII (rFVIIa, 'NovoSeven') is indicated for the treatment of bleeding in patients with haemophilia and inhibitors to factors VIII or IX. However, by virtue of its ability to promote thrombin generation on the platelet surface rFVIIa may also be effective in non-haemophilic bleeding, for example, in patients with thrombocytopenic or oral anticoagulant-induced haemorrhage. Studies in thrombocytopenia indicate that rFVIIa increases the generation of thrombin at the site of injury, leading to the control of bleeding episodes in these conditions. Additionally, preclinical and early clinical evidence has demonstrated the ability of rFVIIa to normalise prothrombin times and international normalised ratios in situations of over-anticoagulation. Although initial observations indicate that rFVIIa may be fast, efficacious, and safe in reversing oral anticoagulant-induced bleeds and those associated with thrombocytopenia, randomised, double-blind, placebo-controlled trials must be conducted to confirm its utility in these and other investigational uses.     

Haemorrhagic complications of thrombocytopenia and oral anticoagulation: is there a role for recombinant activated factor VII?

Recombinant activated factor VII (rFVIIa, ‘NovoSeven’) is indicated for the treatment of bleeding in patients with haemophilia and inhibitors to factors VIII or IX. However, by virtue of its ability to promote thrombin generation on the platelet surface rFVIIa may also be effective in non-haemophilic bleeding, for example, in patients with thrombocytopenic or oral anticoagulant-induced haemorrhage. Studies in thrombocytopenia indicate that rFVIIa increases the generation of thrombin at the site of injury, leading to the control of bleeding episodes in these conditions. Additionally, preclinical and early clinical evidence has demonstrated the ability of rFVIIa to normalise prothrombin times and international normalised ratios in situations of over-anticoagulation. Although initial observations indicate that rFVIIa may be fast, efficacious, and safe in reversing oral anticoagulant-induced bleeds and those associated with thrombocytopenia, randomised, double-blind, placebo-controlled trials must be conducted to confirm its utility in these and other investigational uses.     

Potential role of recombinant factor VIIa as a hemostatic agent

Recombinant factor VIIa (rFVIIa) has been shown to induce hemostasis in hemophilia patients with inhibitors against factor VIII or factor IX independent of factor VIII/factor IX. Factor VIIa binds to tissue factor (TF) exposed at the site of injury and generates, through factor X activation on the TF-bearing cells, enough thrombin to activate factors VIII, V, and XI, as well as platelets. The thrombin-activated platelets provided a perfect template for binding of activated factors VIII, IX, and V, further activation of factor X, and thrombin generation. Factor VIIa in high concentrations binds to thrombin-activated platelets and is capable of activating factor X, thereby generating thrombin independent of the presence of factor VIII or factor IX. Accordingly, rFVIIa has been shown to initiate hemostasis in severe hemophilila patients with inhibitors subjected to major surgery and suffering from serious limb- and life-threatening bleeding. Since rFVIIa enhances thrombin generation-thereby providing the formation of tight, stable fibrin hemostatic plugs resistance to premature lysis-it should be hemostatic in other situations characterized by impaired thrombin generation. A hemostatic effect has been reported in patients with various platelet disorders and factor XI deficiency. Further, a hemostatic effect of rFVIIa has been reported in patients subjected to trauma and extensive surgery who have developed profuse, excessive bleeding resulting in hemodilution and changes in coagulation patterns. rFVIIa was developed to treat bleeding in hemophilia patients with inhibitors against factor VIII or factor IX and has been shown to induce effective hemostasis in most such patients and also in life- and limb-threatening bleeding. It has also been used successfully to stop bleeding in patients who do not have hemophilia but who do have acquired antibodies against factor VIII (acquired hemophilia). rFVIIa initiates hemostasis by forming a complex with TF exposed as a result of vessel wall injury. Pharmacologic doses of rFVIIa can enhance thrombin generation on platelets that are already thrombin-activated, resulting in the formation of full thrombin burst. By enhancing thrombin generation, rFVIIa helps to form tight, stable, fibrin plugs resistant to premature fibrinolysis. This also maintains hemostasis in the absence of factor VIII or factor IX. Pharmacologic doses of rFVIIa may accordingly be of benefit in producing hemostasis in situations other than hemophilia characterized by profuse bleeding and impaired thrombin generation. There is now clinical experience indicating a hemostatic effect in patients with thrombocytopenia and functional platelet defects. rFVIIa has also been successfully used in acute trauma patients with profuse bleedings and in other bleeding situations.     

Emerging off-label uses for recombinant activated factor VII: grading the evidence

Recombinant activated factor VII (rFVIIa) is currently licensed in the United States for treatment of bleeding episodes in patients with deficiencies of factor VIII (FVIII) or IX (FIX) who are refractory to factor replacement because of circulating inhibitors. A 1999 report of its successful use to stop what was deemed to be lethal hemorrhage after an abdominal gunshot wound in a young soldier without pre-existing coagulopathy has prompted exploration of other uses for rFVIIa. The virtual explosion of proposed uses of rFVIIa raises issues not only regarding our understanding of the coagulation system, but also regarding its efficacy, cost-effectiveness, and safety.     

Prerequisites for recombinant factor VIIa-induced thrombin generation in plasmas deficient in factors VIII, IX or XI

BACKGROUND: Recombinant factor VIIa (rFVIIa) used for the treatment of hemophilia A or B patients with an inhibitor is hemostatically effective because it induces thrombin generation (TG), despite grossly impaired FVIII- and FIX-dependent amplification of FX activation. Tissue factor (TF) and or activated platelets were shown to be essential for the rFVIIa activity. OBJECTIVE: To evaluate the relative effects of TF and phospholipids on rFVIIa-induced TG in FVIII-, FIX- and FXI-deficient plasmas. METHODS: Phospholipids had an independent effect that was augmented by TF. The contribution of blood-borne TF in FVIII-, FIX- and FXI-deficient plasma to rFVIIa-induced TG was demonstrated by removing microparticles and use of anti-TF antibodies. RESULTS: At increasing concentrations of rFVIIa, the dependence of rFVIIa-induced TG on TF declined, but the presence of phospholipids was essential. rFVIIa was also shown to activate purified FIX and FX in the presence of phospholipids and absence of TF. rFVIIa-induced TG was dramatically augmented in FVIII- or FIX-deficient plasma in which the level of FVIII or FIX was increased to 1 or 2 U dL(-1). CONCLUSIONS: The data indicate that rFVIIa-induced TG is affected by TF, phospholipids, rFVIIa concentration, and the presence of FVIII and FIX.     

Ongoing NovoSeven trials

Recombinant activated factor VII (rFVIIa, 'NovoSeven' was initially developed for the treatment of bleeding in patients with haemophilia and inhibitors, and is currently licensed in most countries worldwide. The mechanism of action suggests that its enhancing effects in haemostasis are limited to the site of injury and that systemic activation of the coagulation cascade does not occur. These properties, together with anecdotal reports of its beneficial effects in different patient populations with severe bleeds, suggest that rFVIIa may be valuable as a general haemostatic agent. In case reports, rFVIIa has been reported to reduce bleeding in patients with liver disease, thrombocytopenia or thrombocytopathia, trauma those undergoing radical prostatectomy or receiving oral anticoagulant therapy. A number of clinical trials have recently been initiated to collect data on the safety and efficacy of rFVIIa in these patient groups. The beneficial effects of rFVIIa occurring in these studies will support the potential use of rFVIIa as a universal haemostatic agent.     

The emerging role of recombinant activated Factor VII (rFVIIa) in the treatment of blunt traumatic haemorrhage

Recombinant activated Factor VII (rFVIIa; eptacog alpha [activated], NovoSeven) is currently used for the management of a subgroup of haemophilia patients with inhibitors to Factors VIII or IX, and is under investigation as an adjuvant therapy for critical bleeding from other causes, including trauma. rFVIIa has a mode of action founded on physiological coagulation processes, and causes localised haemostasis at injury sites, both spontaneous and traumatic, with the capacity to correct the systemic coagulopathy associated with massive blood loss and its management. This review charts the development of rFVIIa as a new and potent adjuvant therapy for severe bleeding and coagulopathy caused by blunt trauma, where it is reported to produce rapid and significant haemostasis, reducing transfusion requirements and improving clinical outcome.     

Ongoing NovoSeven<Subscript>®</Subscript> trials

Recombinant activated factor VII (rFVIIa, ‘NovoSeven_®’) was initially developed for the treatment of bleeding in patients with haemophilia and inhibitors, and is currently licensed in most countries worldwide. The mechanism of action suggests that its enhancing effects in haemostasis are limited to the site of injury and that systemic activation of the coagulation cascade does not occur. These properties, together with anecdotal reports of its beneficial effects in different patient populations with severe bleeds, suggest that rFVIIa may be valuable as a general haemostatic agent. In case reports, rFVIIa has been reported to reduce bleeding in patients with liver disease, thrombocytopenia or thrombocytopathia, trauma those undergoing radical prostatectomy or receiving oral anticoagulant therapy. A number of clinical trials have recently been initiated to collect data on the safety and efficacy of rFVIIa in these patient groups. The beneficial effects of rFVIIa occurring in these studies will support the potential use of rFVIIa as a universal haemostatic agent.     

The role of recombinant factor VIIa (FVIIa) in fibrin structure in the absence of FVIII/FIX

Summary.  Patients with hemophilia have an impaired thrombin generation and therefore form loose fibrin hemostatic plugs that are easily dissolved by fibrinolysis. This prevents maintained hemostasis in these patients, resulting in a severe bleeding disorder. Recombinant (F)VIIa has been shown to enhance thrombin generation on already thrombin-activated platelets in the absence of FVIII and FIX. An efficacy rate of 80–90% has been found in hemophilia patients with inhibitors against FVIII or FIX both in association with major surgery and in the treatment of serious bleedings. In a model measuring fibrin clot permeability in a platelet-containing system described by Blombäck et al . (1994) this was demonstrated to be dependent on the concentration of FVIII and FIX. The addition of rFVIIa in concentrations of 1.9, 4.8 and 9.6 µg mL⁻¹ normalized fibrin clot permeability. The concentration of 1.9 µg mL⁻¹ of rFVIIa normalized clot permeability in this system and the higher concentrations of rFVIIa added only slightly to the effect. No further decrease in clot permeability was found when rFVIIa in a concentration of 1.9 µg mL⁻¹ was added to a sample with a normal concentration (100%) of FVIII or FIX. Higher concentrations of rFVIIa added to the plasma containing 100% of FVIII or FIX induced only a slight further decrease of fibrin permeability constant, arguing against any unwanted effect of extra rFVIIa on clot permeability in the case of a normal hemostasis. Furthermore, the fibrin network was studied with 3D microscopy and the loose network found in the absence of FVIII or FIX increased in density with increasing FVIII or FIX concentrations. The addition of rFVIIa to FVIII- or FIX-deficient systems altered the network structure, making the fibers thinner and more tightly packed.     

Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors

BACKGROUND: Hemophilic patients with factor VIII (FVIII) and FIX inhibitors suffer from frequent bleeding episodes and reduced quality of life. OBJECTIVES: To evaluate whether secondary prophylaxis with activated recombinant factor VII (rFVIIa) can safely and effectively reduce bleeding frequency as compared to conventional on-demand therapy. METHODS: Thirty-eight male patients entered a 3-month preprophylaxis period to confirm high baseline bleeding frequency (mean > or = 4 bleeds per month). Twenty-two patients were randomized 1:1 to receive daily rFVIIa prophylaxis with either 90 or 270 microg kg(-1) for 3 months, followed by a 3-month postprophylaxis period. RESULTS: Bleeding frequency was reduced by 45% and 59% during prophylaxis with 90 and 270 microg kg(-1), respectively (P < 0.0001); however, there was no significant difference detected between doses. The majority of this reduction was maintained during the postprophylaxis period. Although all types of bleed were similarly reduced, the effect was most pronounced for spontaneous joint bleeds. Patients reported significantly fewer hospital admissions and days absent from work/school during prophylaxis as compared to the preprophylaxis period. No thromboembolic events were reported during prophylaxis. CONCLUSION: Clinically relevant reductions in bleeding frequency during prophylaxis as compared to conventional on-demand therapy were achieved without raising safety concerns. These results provide evidence for the concept of secondary rFVIIa prophylaxis in inhibitor patients with frequent bleeds.     

Long-term prophylaxis in congenital haemophilia with inhibitors - experiences with rFVIIa

A major challenge in the treatment of haemophilia patients is the development of autoantibodies against factor VIII. These patients are at particular risk if spontaneous bleedings or traumata occur or if surgery is necessary. In case of an unsuccessful immune tolerance therapy with high i.v. doses of factor VIII, treatment with recombinant factor VIIa or activated prothrombin complex should be considered. This article summarises data of three patients with severe haemophila A due to an inversion of intron 22 in the FVIII gen. All three patients had autoantibodies against FVIII. The therapy of these patients with rFVIIIa was safe and effective. Furthermore a prophylactic therapy with rFVIIa (at an individual dose of 180-270 microg/kg body weight) reduced the number of spontaneous bleedings in joints and muscles as well as in other locations significantly. The reduced rate of spontaneous bleedings improved the mobility and the quality of life in the young patients studied.     

Acquired haemophilia due to autoantibodies against factor VIII

The acquired haemophilia is caused by formation of autoantibodies which are most frequently directed against factor VIII (FVIII). This disease associated with considerable morbidity as well as mortality occurs preferentially in the elderly. The antibodies lead to a loss of FVIII activity resulting in bleeds especially of soft or subcutaneous tissue or in muscles. Diagnosis: aPTT prolongation and the reduction of the factor activity are of diagnostic importance. However, with respect to bleeding tendency basal activity and inhibitor titre are less meaningful than in inherited haemophilia complicated by inhibitor formation. Therapy is subdivided into treatment of acute bleeds and long-term eradication of the inhibitor. Administration of recombinant FVIIa, high dosed FVIII or activated prothrombin complex concentrates represent approved treatment options of bleeding episodes. Immunosuppressive agents occasionally combined with FVIII administration or immunoadsorption may lead to long-term inhibitor eradication. As CD4(+) T cells as well as anti-idiotypic antibodies appear to be increasingly pathogenetically meaningful new immunomodulating agents might improve the treatment of acquired haemophilia.     

Rituximab in the treatment of acquired haemophilia A in a patient with polymyalgia rheumatica

Acquired hemophilia A is a rare but potentially life-threatening bleeding disorder. It is caused by the development of autoantibodies directed against coagulation factor VIII in adults or elderly patients, who do not have a personal or family history of bleeding. Case: A man (age: 76 years) on prednisone and leflunomide for polymyalgia rheumatica developed spontaneous severe haematomas. The patient was diagnosed with acquired factor VIII deficiency (FVIII activity 1.2%, FVIII inhibitor 31.7 BU). Due to the active bleeding diathesis, treatment was administered with activated prothrombin complex concentrates (FEIBA®, Baxter). Immunosuppressive treatment with a combination of oral prednisone (1 mg/kg daily) and cyclophosphamide (1,5 mg/kg daily) was administered to reduce the FVIII inhibitor. However, after two weeks of treatment, FVIII was only 3% and no clinical improvement was observed. Treatment with the anti CD20 monoclonal antibody rituximab intravenously at 375 mg/m2 once weekly for four consecutive weeks was started. The patient showed rapid clinical improvement following rituximab treatment. He achieved a complete remission defined as return to normal FVIII activity and undetectable FVIII inhibitor titer. After a follow-up of six months no relapse occurred. Conclusion: Rituximab appears an effective and well-tolerated treatment for patients with acquired haemophilia.     

Transfusion medicine service policies for recombinant factor VIIa administration

Recombinant FVIIa (rFVIIa) has been approved for treatment of bleeding in hemophilia patients with inhibitors. It has also been successfully used in nonhemophilia patients with acquired antibodies against FVIII (acquired hemophilia). Pharmacological doses of rFVIIa have been found to enhance the thrombin generation on already activated platelets and, therefore, may also likely be of benefit in providing hemostasis in other situations characterized by profuse bleeding and impaired thrombin generation, such as patients with thrombocytopenia and in those with functional platelet defects. Additionally, it has been used successfully in a variety of less well-characterized bleeding situations, as well as in patients with impaired liver function. To date, case reports, anecdotal experience, and limited clinical trials describe these uses; data from randomized clinical trials are limited. Because of the recent trends in rFVIIa usage in non-approved settings among physicians from various disciplines, significant concerns about its safety, efficacy, and costs have arisen. Additionally, dosing of rFVIIa for these potentially broad clinical applications is not standardized. Currently, the decision on when and where to use rFVIIa for patients with uncontrolled bleeding continues to be one that must be made by individual physicians, assisted by their hospital pharmacotherapeutics and transfusion committees.     

pdFVIII/VWF may be an alternative treatment for old medical patient with acquired haemophilia A and systemic vascular disease?

Acquired Haemophilia is a severe, rare and potentially life-threatening bleeding that affects both males and females with an incidence of 1.5 cases/million/year. Mucocutaneous haemorrhages or haematomas are the typical expression of this disease as a consequence of a decrease in FVIII activity and the presence of a FVIII inhibitor, which differs from congenital haemophilia. We report a case of a 71 year-old-man who presented with spontaneous haematomas and severe anaemia and suffered from vascular disease. At admission, all haemostatic and laboratory data were diagnostic for idiopathic AHA. Treatment with by-passing agents such as rFVIIa was contraindicated because of the risk of thromboembolic events. Despite the fact that administration of FVIII concentrates in AHA is recommended only in patients with an inhibitor titre < 5.0 BU, the physicians decided to use pdFVIII/vWF with corticosteroids in this patient. One month later, the FVIII was within the normal range and the inhibitors had disappeared. In our case, pdFVIII/vWF resulted in a safe and effective alternative for the treatment of acquired haemophilia A in a patient at high thromboembolic risk.     

1-Deamino-8-D-arginine-vasopressin--an alternative in the management of mild haemophilia A and von Willebrand's disease

Intravenous administration of 0.4 micrograms DDAVP/kg body weight in 16 normal controls, 34 patients with haemophilia A and 30 patients with von Willebrand's disease (vWd) was followed by an increase in FVIII: C from 230 to 410%, in FVIIIR:Ag from 160 to 260% and FVIIIR:RC of from 160 to 320%. Additionally, in the patients with vWd, a shortening of the bleeding time and improvement in platelet retention was observed. In 7 haemophiliacs with pretreatment levels of FVIII: C ranging from between 11 and 43% dental extractions were performed successfully after DDAVP whereas in 2 patients with FVIII: C levels of 5 and 6%, respectively, severe bleeding necessitated administration of factor VIII concentrates. In 8 haemophiliacs (FVIII: C between 6.5 and 50%) and 2 patients with vWd (FVIII: C 18 and 36%, respectively) DDAVP enabled minor surgery and successful therapy of spontaneous or traumatic bleeding complications. However, severe postoperative bleeding after stomach surgery in 2 haemophiliacs (FVIII: C 23 and 40%, respectively) and severe menstrual bleeding in one patient with vWd (FVIII: C 15%) required administration of factor VIII concentrates. At present DDAVP therapy should be restricted to minor surgery and non-life-threatening, spontaneous or traumatic bleeding complications in patients with pretreatment FVIII: C levels higher than 10%.     

Recombinant activated factor VII use in the emergency department

Recombinant activated factor VII (rFVIIa) has recently gained wide attention as a potent prohaemostatic agent for patients with excessive or life-threatening blood loss. Originally licensed for the treatment of patients with bleeding haemophilia with antibodies to factor VIII or IX, rFVIIa is now being used on an off-label basis to thwart blood loss in a variety of other clinical situations. Despite concerns over the drug's cost, risk profile and the lack of large-scale clinical trials validating its use, more and more patients are being treated with rFVIIa in the emergency department. With few clinical trials available to guide its administration, emergency physicians must weigh the existing evidence when considering whether to use rFVIIa for their patients with bleeding. This paper reviews the current literature regarding rFVIIa as it pertains to the practice of emergency medicine.